Polymer cements are widely used in reconstructive surgery for the fixation of prostheses, for bone repair and for vertebroplasty. The first cements for bone repair and filling appeared in the 1960s following the research of J. Charley (J. Bone Joint Surge, 1960, 42B:28), on the use of thermosetting pastes based on acrylic monomers, more particularly based on methyl methacrylate (MMA), for fixation of a prosthesis on a femur.
This technique was soon recognized as the standard procedure for the fixation of prostheses. Improvements in the formulation of these cements were made later, in particular by adding radio-opacifying fillers allowing visualization of the cement during and after the procedure, or else by adding antibiotics that are gradually released by the cement, thus reducing the risks of infection.
At present there are about thirty commercial brands of cement formulations for the fixation of prostheses and bone repair approved by the Agence Française de Sécurité Sanitaire des Produits de Santé [French agency for the safety of health products] and the Food and Drug Administration (Lewis G., J Biomed Mater Res Appl. Biomater. 2008, 84B:301).
Two main types of formulations for acrylic cements can be distinguished: formulations for high-viscosity cements, for which the surgeon mixes and moulds the paste by hand, and formulations for cements with low or medium viscosity intended to be injected via a syringe or a trocar, and which are used in particular in bone filling and vertebroplasty (Lewis G., J. Biomed. Mater Res B, 2006, Appl Biomater, 763: 456-468). All the formulations for polymer cements are based on two-phase or multiphase preparations, which the practitioner must mix manually just before use. The term “phase” applies here to any liquid or solid formulation contained and stored separately in a reservoir, such as a liquid solution, a liquid or solid mixture, either homogeneous or of homogeneous appearance at the macroscopic level (stable suspension, mixture of powders, etc.).
Thus, by “two-phase or multiphase formulation” or “two-phase or multiphase preparation” is meant that the different components involved in the preparation of the polymer cements, namely monomers, polymers, radio-opacifying agent, initiator, activator as well as any other additive, are distributed in several phases stored in separate reservoirs (at least two), the phases contained in the different reservoirs being mixed to initiate setting of the cement, just before or during the injection operation. The purpose of these two-phase or multiphase formulations is to avoid the monomers being in contact with the initiator or, even worse, the monomers being in contact simultaneously with the initiator and the activator, thus preventing initiation of the polymerization reaction and rapid, inadmissible caking of the formulations.
A review of this field shows that, still today, nearly all the commercial cements are in the form of a solid, powder phase and a liquid phase, to be mixed (the main ones being Osteopal-V®, Osteo-Firm®, Vertebroplastic®, Simplex®, Cranioplastic®, Palaces®, CMV®, KyphX HV-R®).
The solid phase mainly contains beads of poly(methyl methacrylate) (PMMA) or PMMA copolymers (co-PMMA), an initiator of radical polymerization, generally benzoyl peroxide (BPO), and a radio-opacifying filler, such as barium sulphate (BaSO4) or zirconium dioxide (ZrO2). The liquid phase consists of monomer(s), such as for example methyl methacrylate (MMA), optionally mixed with co-monomers, and a radical activator, generally N,N-dimethyl-p-toluidine (DMPT) when BPO is used in the solid phase (McGraw J K at al. 2003, J Vase Intery Radiol; 14: S311-5).
In these two-phase formulations, the monomers are therefore neither in contact with the initiator, nor with the initiator/activator combination during the storage phase, the mixture being made at the moment of application.
These two-phase formulations, constituted by a liquid phase and a solid phase, which are mixed together to produce the cement just before it is injected, are called “standard formulation” in the present document.
These cements, originally designed for the fixation of prostheses, were applied in vertebroplasty in 1985 (Galibert P et al., 1987, Neurochirurgie, 33: 166). The principle relates to introducing the cement preparation into a damaged vertebra; on hardening in situ, it will constitute a mechanical reinforcement by filling the cavity. The indications for this procedure are, in particular, vertebral angiomas, spinal metastases leading to vertebral fractures, and osteoporotic collapse, which in particular affects women and elderly men.
With the ageing of the population, vertebroplasty is undergoing rapid growth. The number of procedures is estimated at 2 million per year, for a market worth 3 billion dollars. Just in the United States and Europe, 700 000 and 450 000 clinical cases of vertebral fracture are detected per year, respectively.
The surgical technique proper consists of injecting percutaneously, under radiological control, a polymer cement of low or medium viscosity into a pathological vertebra to obtain consolidation of said vertebra. For this procedure, the practitioner generally operates under local anaesthesia, perforating the vertebral body using a trocar, and follows the procedure using radiography. Once the trocar is ideally placed, a radio-opaque acrylic cement, of the same type as those used for operations involving the hip or the knees, is prepared by mixing the various components, and is then injected so as to fill the vertebral body. On hardening by polymerization, the cement will thus reinforce the vertebra.
With most of the commercial cements, to be able to perform vertebroplasty, the practitioner must, in a first manual step, mix the various formulations containing the components of the cement with vigorous stirring, until the cement begins to set, characterized by a rapid increase in its viscosity and its temperature. This preliminary step, on the one hand, exposes practitioners to the toxic vapours of the monomer and of the activator (DMPT) and on the other hand constitutes, owing to its manual character, a known cause of non-uniformity in the properties of the cements obtained, in particular because of inclusion of air bubbles formed under stirring. These bubbles will cause, after polymerization, the appearance of pores, varying in size, and will lead to brittle zones in the material.
The duration of this initial polymerization step depends on the composition of the formulations, on the ambient temperature but also on the manner of stirring and of mixing the different phases, which vary with each technician. This preliminary step, carried out in the presence of the oxygen of the air, may also cause a varying degree of partial deactivation of the radicals initiating the polymerization reaction. The variability associated with this step of manual mixing under air has been reduced by using the method that consists of centrifugation/mechanical mixing of the powder/liquid mixture under moderate vacuum, but this technique requires special equipment in the operating theatre (Wixson, P. I. et al. J. of Arthroplasty, 1987, Vol, 2, Issue 2, 141-149).
The end of this initial step is defined empirically as being the moment when the cement no longer sticks to the practitioner's gloves. The “working” time during which the cement is then usable, i.e. introduced into the syringe and then injected via the trocar, is limited to a few minutes (typically 8 to 15 minutes). A cement for which setting is too advanced risks blocking the trocar, whereas a cement that is too fluid (containing a high proportion of toxic monomer, still unpolymerized) presents the risk of flowing out of the vertebra, causing significant post-operative complications (venous compression, peridural loss, arterial hypotension, etc.). These risks can be reduced by passing a balloon into the vertebra beforehand, this balloon then being inflated in situ to straighten the vertebra and create a more impervious cavity into which the cement is introduced. This is then called kyphoplasty, but this makes the procedure more complex, more difficult and more expensive.
Other approaches have been proposed to improve the procedures and reduce the surgical risks.
Patent application WO2010/005442 relates to preparations of “multi-solution” or else multiphase liquid/liquid cements constituted by two liquid formulations (phases). The liquid formulations described are constituted by solutions (or more precisely suspensions, in many cases), based on monomer (MMA) containing polymer (PMMA) chains in various forms (linear, crosslinked particles, combs), and a radio-opacifying agent; one of the formulations containing in addition the initiator (BPO) and the other the activator (DMPT). These two formulations are placed each in a chamber of a two-chamber injector, installed at the outlet of a mixer in which the two liquid formulations are brought into contact and mixed at the moment of the injection operation. The starting of polymerization of the MMA that follows results from the combined action of BPO and of DMPT on the monomer(s).
A major drawback of this method is the reduced stability of the solution of MMA containing BPO, the decomposition of which into initiator radicals takes place slowly but continuously, even at temperatures of 10° C., or even at lower temperatures, as reported by Sivaram, S. et al., Polymer Bulletin, 1980, 3, 1-2, 27-35. This limits the storage and usage over time of these liquid formulations, the viscosity of which increases even when they are stored in a refrigerator (4° C.). Moreover, it is well known that injection of two phases having different viscosities using a two-compartment syringe is difficult to control and presents risks of inhomogeneity in the distribution of the components of the two phases during mixing, and this inhomogeneity affects the final properties of the cements.
With the same objective, namely to automate the process and reduce the manual operations, application US 2007/0027230 describes devices for preparing, mixing and injecting cements of high viscosity (typically above 500 Pa·s and that may reach 2000 Pa·s after a period ranging from a few minutes to about ten minutes) into the patient's vertebra. The injection devices described are able to apply very high pressures, making it possible to prepare and introduce cements of high viscosity to the vertebra to be treated. Two-phase or single-phase compositions for high-viscosity cements having various hardening rates and hardness characteristics are claimed.
With respect to cements constituted on the basis of two separate phases, one liquid containing monomer, activator and various additives, the other solid containing polymer, initiator and other additives, these correspond to “standard” formulations as they lead to high-viscosity cements.
The single-phase formulations described in application US 2007/0027230 are constituted by a single phase containing one or more polymers without a monomer component. The corresponding “high viscosity” cements do not use any polymerization step and their “hardening” is based solely on the change in thermomechanical properties of the polymers with the temperature. These “all polymer” formulations are constituted by a polymer or a mixture of polymers having softening points (Tg) slightly above body temperature. They are injected at a temperature above the softening point using a device allowing high pressures to be applied. These cements with very high viscosity are called “non-hardening”.
This strategy, based on the design of “high-pressure” injection devices, which may or may not integrate the steps of preparation/mixing of “high-viscosity” cements, allows the absence, or the use of a reduced quantity, of toxic monomer, which limits the risks inherent in its introduction into the patient's body. This approach also makes it possible to limit or even eliminate the temperature peak that characterizes the polymerization step (Tpeak>80° C. in certain methods), avoiding the risks of necrosis of adjacent tissues. However, this technique requires the application of very high pressures (200 atmospheres, or even higher), which constitutes a considerable risk of damage and/or rupture of the vertebrae or bone to be consolidated, which are in a weakened state.
Another problem, encountered in particular in bone repair and in vertebroplasty, concerns the excessive hardness and low compressibility and flexibility of the existing commercial cements, which may lead to new bone fractures through transmission of mechanical stresses. This is relatively frequent at the level of the repaired vertebra, but also at the level of the adjacent vertebrae, to which the stresses are transferred directly without damping. Thus, Grados at all (Rheumatology 2000; 39: 1410-4) reported, in a mean follow-up of four years, that the relative risk of vertebral fracture in the vicinity of a collapsed vertebra increased from 1.44 to 2.27 after vertebroplasty.
Similarly, Cyteval at al. (AJR 1999; 173: 1685-90) detected new vertebral fractures in 25% of cases at the end of six months after treating fractures. In an attempt to correct this problem, cements were developed having characteristics of hardness and of compressibility appropriate to the properties of the vertebra or any other element to be treated.
Thus, application US2007/0027230 cited above, as well as applications WO2010/115138, WO2011/004355 and US2010/0228358, propose special formulations of cements combining, respectively, either particular polymers, such as modified PMMAs that provide porosity, or particles of hydrophilic crosslinked polymers, or else particles of glass or of ceramics in order to modulate the properties of hardness and of compressibility of the cements. Saving exceptions, these cements are prepared by manual mixing of a liquid phase and a solid phase.
Therefore there are still no completely satisfactory methods for preparing and applying formulations leading to acrylic cements displaying optimum properties for vertebroplasty. In particular, there is no method based on the simple application of single-phase preparations for polymer cements excluding any complex operation of mixing phases together.